Coenzyme Q10 is a lipophilic (i.e. hydrophobic) pharmaceutical or nutrient substance with very low solubility in water (practically insoluble in water). Formulations of coenzyme Q10, e.g. for oral administration, are therefore mainly based on the use of oils or similar excipients as the carrier media. The products for oral administration formulated in this way and currently available commercially, such as, for example, Super Bio-Quinone (Pharma Nord, a Danish pharmaceutical company) and GNC preventive nutrition CoQ-10 (General Nutritional Corp.) have a very low bioavailability.
Common soft capsule formulations are solutions in oils or suspensions in lipophilic systems. Bioavailability studies from various publications have shown low bioavailability of Q10 in those conventional formulations. It is also known that conventional soft capsule products of Q10 have zero or very low dissolution.
In the case of Q10, in the past it has been dissolved in oils and emulsified by surfactants. However, conventional emulsions resulted from self-emulsifying systems often gave coarse droplets that are at micron (μ) scale. The droplet size distributions are often broad, ranging from about 1 to 100 micron.
The coarse droplet size and broad distribution are believed to be the main contributors to inconsistent dissolution behavior of coenzyme Q10 in soft capsule formulations. This behavior is believed to be dependent on density of the droplets which in turn are dependent on the ratio of oil to surfactants. Furthermore, the formation of conventional emulsions requires strong agitation. This is difficult to attain by the rotational speed of dissolution paddles (commonly less than 100 rpm).
In contrast to conventional emulsions, microemulsions are isotropic and produce droplet sizes in the nanometer range, typically less than 100 nm. The polydispersity is often narrow. The formation of microemulsions is typically fast, thermodynamically stable and thus, does not require vigorous stirring. It is a common procedure in dissolution testing that samples withdrawn are filtered through a 0.45 micron (or 450 nm) membrane filter. A microemulsion would have no problem in passing through the filter, while a conventional emulsion would risk broken droplets and active ingredients retained on the filter due to its hydrophobicity.
It is well known that soft capsules are limited by the amount of water that is in fill formulations, such that microemulsions cannot be encapsulated in the typical shell formulation. Accordingly, it is only practical to encapsulate the precursors of microemulsions that do not contain water, and that are capable of forming microemulsions upon contact with water. Such precursors are referred to as Self-Microemulsifying Drug Delivery Systems or SMEDDS.
Prior fill formulations in the form of oil-based soft capsules continue to have difficulty providing optimum bioavailability owing to the low solubility of CoQ10, and the tendency of the product to crystallize over time.
The problems to be solved by the present invention include increasing bioavailability while preventing crystallization of the CoQ10 active ingredient upon release. The present invention is further directed to providing dosage forms providing enhanced dissolution of Q10 for improved bioavailability. In addition, the present invention provides fill formulations that may be used effectively in soft capsule dosage forms.